Aggressiveness in Italian Children with ADHD: MAOA Gene Polymorphism Involvement.

ADHD is a neurodevelopmental disorder that children and adults can develop. A complex interplay of genetic and environmental factors may underlie interindividual variability in ADHD and potentially related aggressive behavior. Using high-resolution molecular biology techniques, we investigated the impact of some MAOA and SLC6A4 variations on ADHD and aggressive behavior in a group of 80 Italian children with ADHD and in 80 healthy controls. We found that homozygous genotypes of MAOA rs6323 and rs1137070 were associated with an increased risk of ADHD (p = 0.02 and p = 0.03, respectively), whereas the heterozygous genotypes (GT of rs6323 and CT of rs1137030) (p = 0.0002 and p = 0.0006) were strongly linked to a lower risk of developing this disorder. In patients with aggressive behavior, we highlighted only a weak negative association of both MAOA polymorphisms (heterozygous genotypes) with aggressiveness, suggesting that these genotypes may be protective towards specific changes in behavior (p = 0.05). Interestingly, an increase in the GG genotype of rs6323 (p = 0.01) and a decrease in GT genotype (p = 0.0005) was also found in patients without aggressive behavior compared to controls. Regarding 5HTT gene genotyping, no allele and genotype differences have been detected among patients and controls. Our work shows that defining a genetic profile of ADHD may help in the early detection of patients who are more vulnerable to ADHD and/or antisocial and aggressive behavior and to design precision-targeted therapies.

Impact of HLA Class I Antigen, Killer Inhibitory Receptor, and FCGR3A Genotypes on Breast Cancer Susceptibility and Tumor Stage.

BACKGROUND: The identification in breast cancer (BC) of novel genetic biomarkers regulating natural killer (NK) cell function, including the HLA, KIR, and CD16A (FCGR3A), may be still a challenge. OBJECTIVE: We aimed to evaluate whether the combined effect of these polymorphisms has an impact on BC susceptibility and progression. METHODS: 47 BC Italian patients and healthy individuals (39 females and 66 males/females) were genotyped by Sanger sequencing (HLA-C exon 2-4 and FCGR3A-158V/F, 48L/R/H) and PCR-SSP typing (KIR genes). RESULTS: HLA-C gene allele analysis showed the group C1, with HLA-C*07:02:01 allele, to be significantly associated with tumor progression (16.7% vs. 4.0%, p=0.04, OR=4.867), and instead, group C2, with HLA-C*05:01:01, was protective against disease susceptibility (0.0% vs. 7.2%, p=0.019, OR=0.087). In addition, we highlighted a significant reduction of the KIR2DS4ins in BC patients (pcorr.=0.022) and an increased combined presence of KIR2DL1 and KIR2DS1 genes in advanced BC patients compared to earlier stages (66.7% vs. 19.2%, p=0.002). The concurrent lack of KIR2DL2 and KIR2DS4 genes in the presence of HLA-C2 alleles was significantly associated with increased susceptibility to BC (p=0.012, OR=5.020) or with lymph node involvement (p=0.008, OR=6.375). Lastly, we identified different combinations of the FCGR3A-48/158 variants and KIR genes in BC patients compared to controls. CONCLUSION: Our findings suggest that in the development of BC probably exists a disorder of the NK innate immunity influenced by KIR/HLA-C gene content and FCGR3A-158 polymorphisms and that the combined analysis of these biomarkers might help predict genetic risk scores for tailored screening of BC patients in therapy.

The Role of CD1 Gene Polymorphism in the Genetic Susceptibility to Spondyloarthropathies in the Moroccan Population and the Possible Cross-Link with Celiac Disease.

Spondyloarthropathies (SpA) are a group of chronic inflammatory disorders usually affecting the axial spine and asymmetrical peripheral joints. Strong evidence links genetic and environmental factors to SpA pathogenesis. The HLA-B27 is the most important genetic factor associated with SpA. Nevertheless, the involvement of other HLA and non-HLA loci has been also reported. Some patients with SpA may also manifest features of celiac disease (CeD), thus suggesting a genetic overlap across these autoimmune diseases. Recently, CD1 glycoproteins, a class of molecules able to bind and present non peptidic antigens to T cells, aroused interest for their contribution to the pathogenesis of CeD. Therefore, to evaluate whether functional polymorphisms of CD1A and E genes also influence susceptibility to SpA, we analyzed 86 patients from Morocco affected by SpA and 51 healthy controls, using direct sequencing analysis. An increase of CD1E*01/01 homozygous genotype (p = 0.046) was found in SpA, compared with controls. CD1E*01/01 genotype was associated particularly to patients with sacroiliac joints/spine/peripheral joints pain (p = 0.0068), while a decrease of CD1E*01/02 genotype was evidenced compared to controls (p = 0.0065). Results from haplotypes analysis demonstrated that CD1A*02-E*02 decreased the risk of SpA, while CD1A*02-E*01 increased risk to develop disease. Our data indicate a relationship between CD1 genes and susceptibility to SpA in the Moroccan population and suggest the existence of shared genetic risk loci across SpA and CeD that might be useful to explain common pathogenetic features and define novel therapeutic strategies.

Gene- and Gender-Related Decrease in Serum BDNF Levels in Alzheimer's Disease.

Brain-derived neurotrophic factor (BDNF) has a protective role in Alzheimer's disease (AD). Oxidative stress and inflammatory cytokines are potentially implicated in AD risk. In this study, BDNF was detected in serum of AD and mild cognitive impairment (MCI) patients and investigated in association with gene polymorphisms of BDNF (Val66Met and C270T), of some oxidative stress-related genes (FOXO3A, SIRT3, GLO1, and SOD2), and of interleukin-1 family genes (IL-1α, IL-1ß, and IL-38). The APOE status and mini-mental state examination (MMSE) score were also evaluated. Serum BDNF was significantly lower in AD (p = 0.029), especially when comparing the female subsets (p = 0.005). Patients with BDNFVal/Val homozygous also had significantly lower circulating BDNF compared with controls (p = 0.010). Moreover, lower BDNF was associated with the presence of the T mutant allele of IL-1α(rs1800587) in AD (p = 0.040). These results were even more significant in the female subsets (BDNFVal/Val, p = 0.001; IL-1α, p = 0.013; males: ns). In conclusion, reduced serum levels of BDNF were found in AD; polymorphisms of the IL-1α and BDNF genes appear to be involved in changes in serum BDNF, particularly in female patients, while no effects of other gene variants affecting oxidative stress have been found. These findings add another step in identifying gender-related susceptibility to AD.

Longitudinal monitoring of mRNA levels of regulatory T cell biomarkers by using non-invasive strategies to predict outcome in renal transplantation.

BACKGROUND: Acute T-cell mediated rejection (aTCMR) is still an issue in kidney transplantation, for it is associated with chronic rejection, graft loss, and overall worse outcomes. For these reasons, a standard non-invasive molecular tool to detect is desirable to offer a simpler monitoring of kidney transplant recipients (KTRs). The purpose of our study was to examine, in peripheral blood before and after transplantation, the expression patterns of regulatory T cell (Treg)-related genes: the forkhead box P3 (FOXP3) and the two CTLA-4 isoforms (full-length and soluble) to predict acute rejection onset, de novo donor-specific antibodies (DSA) development and renal dysfunction 1 year after transplantation. METHODS: We profiled by using a relative quantification analysis (qRT-PCR) circulating mRNA levels of these biomarkers in peripheral blood of 89 KTRs within the first post-transplant year (at baseline and 15, 60 and 365 days, and when possible at the acute rejection) and compared also the results with 24 healthy controls. RESULTS: The three mRNA levels drastically reduced 15 days after transplantation and gradually recovered at 1 year in comparison with baseline, with very low levels at the time of aTCMR for FOXP3 (RQ = 0.445, IQR = 0.086-1.264, p = 0.040), maybe for the pro-apoptotic role of FOXP3 during inflammation. A multivariate Cox regression analysis evidenced a significant relation between aTCMR onset and thymoglobuline induction (HR = 6.749 p = 0.041), everolimus use (HR = 7.017, p = 0.007) and an increased risk from the solCTLA-4 expression at 15 days, mainly considering recipients treated with Mycophelolic acid (HR = 13.94 p = 0.038, 95%CI:1.157-167.87). Besides, solCTLA-4 also predisposed to graft dysfunction (eGFR< 60 mL/min/1.73m2) at 1 year (AOR = 3.683, 95%CI = 1.145-11.845, p = 0.029). On the other hand, pre-transplant solCTLA-4 levels showed a protective association with de novo DSAs development (HR = 0.189, 95%CI = 0.078-0.459, p < 0.001). CONCLUSIONS: mRNA levels of Treg-associated genes, mainly for solCTLA-4, in peripheral blood could put forward as candidate non-invasive biomarkers of cellular and humoral alloreactivity in clinical transplantation and might help shape immunosuppression, tailor monitoring and achieve better long-term outcomes of kidney transplantation in the wake of "precision medicine".

CD1 gene polymorphism and susceptibility to celiac disease: Association of CD1E*02/02 in Moroccans.

CD1 glycoproteins are a class of antigen presenting molecules that bind and present non-peptidic antigens (lipids and glycolipids) for immune recognition. CD1 polymorphisms, although limited, could have a critical role in antimicrobial, anticancer, and autoimmune responses and disease susceptibility. Ethnic differences and interactions between genetic and environmental factors make it attractive the study of these molecules in autoimmune inflammatory disorders, such as celiac disease (CD), in which a strong genetic predisposition (HLA-DQ2/DQ8) and pressure of environmental factors have a central role. CD1A, CD1D and CD1E polymorphisms in exon 2 were assessed in patients from Morocco affected by CD, using direct sequencing analysis, in order to investigate possible associations with the disease in a North African population. Differences in genotype and haplotype distribution of CD1E between celiac patients and controls were found: in particular, an increase of CD1E*02/02 homozygous (OR 2.93, CI 1.30-6.59, p = 0.007) and CD1A*02-E*02 estimated haplotypes in CD, compared with controls. Frequencies of CD1A and CD1D genotypes/alleles were not different between groups. CD1E*02/02, previously suggested as a potential immune protective genotype to malaria susceptibility, could be an additional gene involved in celiac risk in this geographic area.

Breast Cancer Is Associated with Increased HLA-DRB1*11:01 and HLA-DRB1*10:01 Allele Frequency in a Population of Patients from Central Italy.

The relationship between HLA-DRB1 allele polymorphism and breast cancer (BC) development is still unclear and needs further investigation. To address this issue, we analyzed HLA-DRB1 allele frequency (AF) by sequence-based typing (SBT) in 47 patients from central Italy with BC and 156 sex and age-matched healthy controls. Two hundred ninety-seven individuals from the same region were utilized as historical controls. Pearson's chi-square analysis with Yate's correction or Fisher's Exact test with Bonferroni's correction, as appropriate, were used to compare HLA-DRB1 AF differences in patients and controls. A total of 36 HLA-DRB1 alleles were identified. A detailed study showed that HLA-DRB1*11:01 and HLA-DRB1*10:01 alleles are significantly associated with increased BC risk. In particular, HLA-DRB1*11:01 AF was significantly higher in patients with BC than in healthy females and historical controls, even following Bonferroni's correction (stage I-II BC patients vs historical controls p<0.00; stage III-IV BC patients vs female healthy controls p=0.025 and historical controls p<0.00). The HLA-DRB1*10:01 allele was also positively associated with BC as evidenced by a significantly higher AF in patients with BC than in healthy controls (BC patients stage I-II vs historical controls corrected p =0.01). These results suggest that both HLA-DRB1*11:01 and HLA-DRB1*10:01 AF could represent interesting markers in patients at risk of developing BC.

The Role of Gender-specific Cytokine Pathways as Drug Targets and Gender- specific Biomarkers in Personalized Cancer Therapy.

The definition of personalized treatments in tumor disease could lead to an improvement of the therapeutic success rate. Therefore, biomarkers are urgently required in order to select the patients that could benefit from adjuvant therapies in the initial phase of the disease and to better define and treat the clinical/therapeutic subgroups in the advanced pathological phases. Disregulation of cytokine physiological network is directly involved in the genesis and progression of tumors. Cytokines are of central importance in the regulation of immune system, but they are rarely released singly: each cytokine is able to induce the production of many other factors leading to a network in which they cooperate with other cell regulators such as hormones and neuropeptides. For these reasons the research must be directed to the evaluation of the interrelationships between the different cytokines and their respective pathways, as well as their contribution to the disease aetiology and progression in order to identify real and effective drug targets and biomarkers. The T CD4+ helper cells (Th) have various subpopulations, among which Th1, Th2, Th3, Th9 and Th17, respectively produce cytokines. It has become clear that disorders within the interactions of the network of these cytokines can produce neoplastic diseases. Furthermore, studies focusing on gender have shown that the homeostasis of the immune system is controlled by pathways of cytokines that are different between sexes and defined for this reason "genderspecifics". Therefore, this perspective article aims to highlight the significance of these cytokine pathways in order to identify new clinical strategies and personalized therapy in neoplastic diseases.

Role of KIR and CD16A genotypes in colorectal carcinoma genetic risk and clinical stage.

BACKGROUND: NK cell cytotoxicity is regulated by the types of the interaction between killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands on target cells and the different binding affinity of the Fcγ receptor IIIA (CD16A) for IgG-coated tumor cells. Thus, it is conceivable that KIR and CD16A gene contents may contribute to the function of NK cells by modulating an immune response in the colorectal carcinoma (CRC) microenvironment. This hypothesis is supported by recent evidence suggesting that NK cells improve the clinical course of CRC patients by enhancing the anti-CRC effect of CD8 + T cells. This information provides the rationale to test the hypothesis whether the independent KIR segregation and specificity, as well as CD16A gene polymorphisms, have an impact on CRC. METHODS: Using polymerase chain reaction-sequence-specific primers (PCR-SSP) and sequence-based typing (SBT), we investigated KIR/HLA-C complex and CD16A (48H/R/L,158V/F) gene polymorphisms in 52 CRC patients and 61 local healthy controls (LCTRs). RESULTS: The allele frequency (AF) of at least five activating KIR (aKIRs) of the B haplotype (p = 0.036, OR 0.204), KIR2DL2 (p = 0.047, OR 0.2616), and KIR2DS2 genes (5.8 vs LCTR 13.8 % and vs. Fasano's CTR 16.3 %, p = 0.05, OR 0.3145), in the absence of their cognate HLA-C1 ligands, were significantly associated with a reduced genetic risk of CRC. In contrast, CD16A-48H polymorphism was positively associated with an increased genetic risk of CRC (p = 0.05, OR 2.761). The latter was also found to be correlated with advanced stages of disease [III and IV (p = 0.03, OR 3.625)]. CONCLUSIONS: Our data suggest that the analysis of aKIRs and KIR2DL2 gene and CD16A-48H may be of interest for the identification of individuals at reduced and increased genetic risk of CRC, respectively.

CD1A, D and E gene polymorphisms in a North African population from Morocco.

CD1 molecules are specialized in capturing and presenting lipids and glycolipids to distinct subsets of T and NKT cells. Glycolipid presentation could play a significant role in the immune response against microbial infections. There are five closely linked CD1 genes in humans, named CD1A, B, C, D, and E, which all show a limited polymorphism. In this study, exon 2 polymorphisms of CD1A, CD1D and CD1E were investigated and allele, genotype and haplotype frequencies of these loci were reported in a Moroccan population. A comparison with allele, genotype and haplotype frequencies observed in other geographic areas was also performed. Results confirmed the presence of ethnic differences in CD1 polymorphism, mainly in CD1D (in this population two additional CD1D variant alleles, CD1D(∗)03 and CD1D(∗)04, were described) and E genes. These data could be useful to evaluate a possible pathogenetic role of CD1 in diseases. Increasing the knowledge in this field may offer possibilities for the development of new immunotherapeutic approaches.

MICA∗078: A novel allele identified in a Moroccan individual affected by celiac disease.

A novel MICA allele, MICA(∗)078, has been identified during HLA/MICA high resolution typing of Moroccan patients with celiac disease. MICA(∗)078 shows an uncommon variation at a highly conserved nucleotide position (nt 493, G → A), resulting in one amino acid change at codon 142 (V → I) of MICA gene (compared to MICA(∗)002:01), located in the α2-domain, in which V142 is the common residue.

HLA-DRB1*13:01 allele in the genetic susceptibility to colorectal carcinoma.

Increasing evidence suggests that HLA-DRB1 alleles reduce or increase the risk of developing ulcerative colitis-associated colorectal carcinoma (CRC) tumors. However, the role of HLA-DRB1 locus on the susceptibility to develop CRC tumor, in the absence of a history of inflammatory bowel diseases (IBDs), is unclear. The aim of our study was to determine whether HLA-DRB1 alleles are associated with IBD-independent CRC tumor. HLA-DRB1 allele polymorphisms were identified by sequence-based typing method in 53 CRC patients and 57 sex- and age-matched healthy Caucasian controls. Pearson's chi-squared analysis with Yate's correction or Fisher's exact test with Bonferroni's correction, as appropriate, were used to compare the allele frequency (AF) differences of HLA-DRB1 in patients and controls. A total of 29 HLA-DRB1 alleles were recognized. A detailed study of these alleles allowed to identify DRB1*13:01 and DRB1*11:01 alleles that were significantly associated with an increased and reduced risk to develop CRC tumor, respectively. AF of DRB1*13:01, in CRC patients, was significantly higher than that of healthy controls, even following Bonferroni's correction (p = 0.029). In contrast, the presence of the DRB1*11:01 allele was negatively associated with CRC tumor as evidenced by the significantly lower AF in CRC patients than that of healthy controls (p = 0.005). However, following Bonferroni's correction, the AF of DRB*11:01 lost its statistical significance. These results suggest that HLA-DRB1*13:01 allele could be a potential marker for predicting genetic susceptibility to CRC tumor. In contrast, the protective role of DRB1*11:01 remains unclear.

Ageing gender-specific "Biomarkers of Homeostasis", to protect ourselves against the diseases of the old age.

Low-grade inflammatory state causes the development of the principal chronic-degenerative pathologies related with ageing. Consequently, it is required a better comprehension of the physiologic origins and the consequences of the low-grade inflammatory state for the identification of 1) the basic mechanisms that lead to the chronic inflammatory state and, after that, to the progression toward the pathologies and 2) the parallel identification of the prognostic biomarkers typical of these passages. These biomarkers could bring to several improvements in the health quality, allowing an early diagnosis and more effective treatments for: a) the prevention strategies on the healthy population, to assure a healthy longevity and b) the identification of personalized treatment in patients, to assure the benefit of the therapy. For the identification of these biomarkers it is necessary to consider that the ageing processes produce alterations of the physiologic systems and that these modifications compromise the communications between these networks: this state constitutes an obstacle for an appropriate physiologic homeostasis, that plays a fundamental role for the safeguard of the health. It is also to be considered that immune senescence affects both men and women, but it does it in different ways: a sexual dimorphism of immune pathways in the setting of immune response homeostasis is normally present, as we previously underlined. Therefore we hypothesize that, in order to prevent the development of the chronic-degenerative pathologies related with ageing, it is important to identify "Biomarkers of Homeostasis " specific for each gender: these are biologic molecules that should be measurable in a practical and no-invasive way and whose variations can quantify the male and female risk of losing the physiologic system homeostatic capacity. This competence is not only critical in the control of inflammation, but it is also prognostic for the passages from low-grade inflammatory state to the chronic inflammation and to the progression toward the degenerative pathologies. Beginning from the actual results, our intent is 1) to discuss and underline the importance of these new research perspectives in the definition of ageing gender-specific clinical "Biomarkers of Homeostasis" and 2) to propose homeostasis biomarkers, already present in the research results.

The discovery of how gender influences age immunological mechanisms in health and disease, and the identification of ageing gender-specific biomarkers, could lead to specifically tailored treatment and ultimately improve therapeutic success rates.

The control of human health and diseases in the elderly population is becoming a challenge, since mean age and life expectation are progressively increasing as well as chronic degenerative diseases. These disorders are of complex diagnosis and they are difficult to be treated, but it is hoped that the predictive medicine will lead to more specific and effective treatment by using specific markers to identify persons with high risk of developing disease, before the clinical manifestation. Peripheral blood targets and biomarkers are currently the most practical, non-invasive means of disease diagnosing, predicting prognosis and therapeutic response. Human longevity is directly correlated with the optimal functioning of the immune system. Recent findings indicate that the sexual dimorphism of T helper (Th) cytokine pathways and the regulation of Th cell network homeostasis are normally present in the immune response and undergoes to adverse changes with ageing. Furthermore, immune senescence affects both men and women, but it does not affect them equally. Therefore, we hypothesize that the comprehension of the interferences between these gender specific pathways, the ageing immunological mechanism in pathological or healthy state and the current therapies, could lead to specifically tailored treatment and eventually improve the therapeutic success rates. Reaching this aim requires the identification of ageing gender-specific biomarkers that could easily reveal the above mentioned correlations.

A gender-related action of IFNbeta-therapy was found in multiple sclerosis.

BACKGROUND: Understanding how sexual dimorphism affects the physiological and pathological responses of the immune system is of considerable clinical importance and could lead to new approaches in therapy. Sexual dimorphism has already been noted as an important factor in autoimmune diseases: the aim of this study was to establish whether sexual dimorphism in autoimmune diseases is the result of differing pathways being involved in the regulation of T-helper (Th) cell network homeostasis. METHODS: We focused on sexually dimorphic changes in the immune response in multiple sclerosis (MS) patients in order to ascertain how these alterations relate to the pathway regulation of the cytokine homeostasis and the Th cell networks. We studied antigen presenting cell (APC)-dependent T cell activation in groups of healthy subjects, in patients under interferon (IFN) ß-therapy and untreated. Cytokines, soluble (s) CD30 and the expanded disability status scale (EDSS) were used as biomarkers for T cell differentiation and neurological deficit. RESULTS: The data confirm our belief that sexual dimorphism in autoimmune diseases is the result of differing pathways that regulate Th cell network homeostasis: interleukin (IL) 6 pathways in women and IFNγ pathways in men. Given the increased susceptibility of women to MS and the significance of IL6 in the autoimmune process compared to IFNγ, it is logical to assume that IL6 pathways are in some way implicated in the prevalence of autoimmune diseases in women. Indeed, our data indicate that IL6 pathways are also involved in T regulatory (Treg) cell imbalance and an increase in neurological deficit in both men and women groups of MS patients, underlining the autoimmune etiology of multiple sclerosis. In further support of differing cytokine pathways in men and women, we noted that the efficacy of IFNß-treatment in the re-establishment of Th-network balance and in the delaying of the neurological disability progression is linked to the IL6 pathway in women, but to the IFNγ pathway in men. Lastly, we also identified specific gender biomarkers for the use in therapy. CONCLUSIONS: The identification of gender-specific drugs is of considerable importance in translational medicine and will undoubtedly lead to more appropriate therapeutic strategies and more successful treatment.

The potential role of thioredoxin 1 and CD30 systems as multiple pathway targets and biomarkers in tumor therapy.

Our progress in understanding pathological disease mechanisms has led to the identification of biomarkers that have had a considerable impact on clinical practice. It is hoped that the move from generalized to stratified approaches, with the grouping of patients into clinical/therapeutic subgroups according to specific biomarkers, will lead to increasingly more effective clinical treatments in the near future. This success depends on the identification of biomarkers that reflect disease evolution and can be used to predict disease state and therapy response, or represent themselves a target for treatment. Biomarkers can be identified by studying relationships between serum, tissue, or tumor microenvironment parameters and clinical or therapeutic parameters at onset and during the progression of the disease, using systems biology. Given that multiple pathways, such as those responsible for redox and immune regulation, are deregulated or altered in tumors, the future of tumor therapy could lie in the simultaneous targeting of these pathways using extracellular and intracellular targets and biomarkers. With this aim in mind, we evaluated the role of thioredoxin 1, a key redox regulator, and CD30, a cell membrane receptor, in immune regulation. Our results lead us to suggest that the combined use of these biomarkers provides more detailed information concerning the multiple pathways affected in disease and hence the possibility of more effective treatment.

Gender-specific cytokine pathways, targets, and biomarkers for the switch from health to adenoma and colorectal cancer.

Studies focusing on gender have shown that differences exist in how the immune system responds to disease and therapy. Understanding how gender influences immunological mechanisms in health and disease and identifying gender-specific biomarkers could lead to specifically tailored treatment and ultimately improve therapeutic success rates. T helper1 (Th1) and Th2 cytokines (Th1/Th2) have pivotal roles in the homeostasis of Th1 and Th2 cell network functions in the immune response but sex steroids affect Th1/Th2 production in different ways and a natural sexual dimorphism in the immune response has been shown. In order to investigate these differences further, we developed Th-cytokine data-driven models of the immune response and evaluated healthy subject peripheral blood samples. Independent cohorts of colorectal cancer and adenoma patients were also studied for comparison purposes. Our results show that the interferon (IFN)γ production pathway for immune response homeostasis is specific to men whilst the interleukin- (IL-) 6 production pathway for immune response homeostasis is specific to women. The IL-10 pathway for restoring immune system resting homeostasis was common to both but was controlled by the respective gender-specific pathways. These gender pathways could well be used as targets and biomarkers in translational research into developing new clinical strategies.

Are immunological mechanisms involved in colon cancer and are they possible markers for biotherapy improvement?

This paper focuses on our data on colon cancer patients. Our overall results lead us to believe that the suppressive effect of specific cytokines in colon cancer patients alters the functionality of TH1 and TH2 subsets of CD4+ T-cells, with an expansion of TH2 cells and a malfunctioning of TH1 cells. This immunological disregulation appears to increase with stage progression, suggesting a direct role in the mechanisms that allow the tumour to locate and expand within the host. It is also clear that in order to identify disease markers and generate an in vivo immune response that corrects the imbalance between TH1 and TH2 cells, we need to understand how tumour mechanisms cause this imbalance to begin with.

The study of a patient's immune system may prove to be a useful noninvasive tool for stage classification in colon cancer.

Therapy, and, therefore, prognosis, is strictly related to cancer stage, and hence, screening tests that can contribute to the early classification of disease stage represent a step forward in treatment. Unfortunately, few prognostic indices are available, especially noninvasive ones. Our study of the physiological network of the immune response, however, leads us to believe that it may well be possible to define immunological indices for the classification of cancer stage using blood parameters. In this paper, we show how the study of a patient's immune system can be used as a noninvasive tool for early-stage classification.

Colon cancer and gene alterations: their immunological implications and suggestions for prognostic indices and improvements in biotherapy.

Studies have shown that changes occur in c-Ki-ras, p53, and Bcl2 gene structure and function during the various stages of human colon carcinogenesis. Alterations of these genes are responsible for the establishment of a state of continuous stimulus for cell division and apoptotic inhibition at physiological and pharmacological levels. This paper focuses on the results of our research aimed at investigating how these gene alterations influence tumoral mechanisms on an immunological level and how immunological parameters can be used as prognostic markers for the passage of normal tissue to adenoma and adenoma to carcinoma. Overall, our data suggest that an alteration in the c-Ki-ras gene results in a switch to a suppressive type of immune response, determining an impairment of immune cell activation at both antigen- presenting-cell and T-cell levels. c-Ki-ras gene mutations, p53 deletions, and Bc12 expression, on the other hand, can be used as prognostic markers for the passage of normal tissue to adenoma and adenoma to carcinoma. The p53 oncogene does not appear to impair patients' immunological response further. In conclusion, an evaluation of c-Ki-ras, rather than p53 gene alterations, would seem to be more relevant in colon cancer prevention programs and biotherapy improvement.